Abstract This project has the long-term potential to exploit the differences in taste mechanisms between insects and mammals to develop new strategies to control insect disease vectors that infect hundreds of millions of people annually. In addition, this research explores unexpected similarities between insect and mammalian taste that are evolutionarily conserved. This project will exploit the vast array of tools provided by the fruit fly, Drosophila melanogaster, to address fundamental, longstanding questions in the field of contact chemosensation. The aims will employ an usually diverse combination of approaches, including electrophysiology, Ca2+ imaging, behavior, molecular genetics and cell biological approaches. Aim 1 tests the idea that there exists a signaling pathway that functions in the detection of low levels of bitter compounds, and which bears previously unrecognized similarity to mammalian sweet, bitter and umami taste transduction. The capacity to taste aversive compounds is essential for survival, and high levels of many noxious chemicals are detected through so-called ?gustatory receptors,? which are insect ligand-gated channels distinct from mammalian taste receptors. In addition, TRP channels are also employed to sense bitter compounds. Aim 1 will test the idea that a G-protein coupled receptor (GPCR) couples to a TRP channel in bitter responsive gustatory receptor neurons, and enables flies to sense noxious chemicals at low levels. Thus, despite the striking differences in some mechanisms of taste reception between insects and humans, aim 1 is to define a GPCR/TRP dependent taste transduction pathway in an insect. However, the specific GPCRs that appear to initiate taste transduction in the fly are highly unexpected. Aim 2 concerns a well-known and highly conserved behavior in which animals are attracted to low salt foods and reject foods with high salt. The first aim leverages our recent discovery as to how low and high Na+ taste perceptions are differentially encoded in gustatory receptor cells, and thereby induce distinct behavioral responses. An ionotropic receptor (IR76b) is the low salt sensor, but the high salt receptor remains unknown. Aim 2 is to define the high Na+ receptors, and address whether they form a multi- subunit cation channel. Another behaviorally conserved, but poorly characterized gustatory modality is Ca2+ taste. Aim 3 is to reveal the enigmatic Ca2+ receptors that endow animals with the ability to taste Ca2+. Finally, aim 4 is to dissect the molecular and cellular mechanism through which food texture affects taste preferences. This would break important new ground since the molecular basis for food texture detection in animals is as yet completely unexplored. Aim 4 will test the idea that the hardness of food is detected through the Drosophila homolog of ?transmembrane channel-like? (TMC) proteins, which in mammals are implicated as subunits of a channel complex in auditory hair cells. In summary, in those cases in which insect and human receptors are distinct, the differences can be exploited to develop strategies to control disease vectors. Conversely, focusing on flies also offers to reveal evolutionarily conserved gustatory detection mechanisms.